Souda et al., U.S. Pat. No. 5,045,552, incorporated by reference herein, describes compounds that inhibit an H+/K+-ATPase present in the stomach. These compounds are useful for treatment of peptic ulcers and other disorders associated with secretion of gastric acid, such as heartburn and gastroesophageal reflux. For example, one such compound has the following structure: and includes pharmaceutically acceptable salts of the compound. This compound is referred to herein as Compound 1.
It is desirable when preparing reconstituted solutions of such anti-ulcerative compounds that are suitable for intravenous administration, that the solubilized compounds exhibit physical and chemical stability for at least between about 6 and about 12 hours at room temperature. It has been found by the present inventors that anti-ulcerative compounds such as Compound 1 and the compounds described by general formula I below discolor when they are reconstituted, i.e., dissolved, in aqueous solutions, particularly in solutions suitable for intravenous administration, e.g., 5% dextrose or 0.9% saline. Such solutions quickly turn yellow to yellow-brown.
The compounds of the present invention have been determined to be more potent H+/K+-ATPase inhibitors than omeprazole sodium. However, in order to provide clinically useful pharmaceutical formulations of the compounds disclosed herein for intravenous administration, it is first necessary to provide formulations for lyophilization and intravenous administration that do not degrade physically, chemically and/or demonstrate a change in color.